Phenylalkanol derivatives



ited

PHENYLALKANDL DERKVATIVES Henri Morren, Forest-Brussels, Belgium, assignor to Union Chimique Beige, S.A., Brussels, Belgium, a corporation of Belgium No Drawing. Application December 23, 1957 Serial No. 704,298

Claims priority, application Belgium January 21, 1957 12 Claims. (Cl. 260-2475) The present invention relates to new nitrogenous derivatives of phenylalkanols of the general formula C Hi-N X wherein R is a hydrogen atom or a methyl group, n is an integer from 1 to 3,

N\X represents an aliphatic or heterocyclic secondary amine residue.

The invention also concerns the preparation of these products and of their salts.

These products have interesting pharmacological properties, notably marked ataraxic properties. In addition, clinical observations show that they produce no unpleasant secondary eifects, such as drowsiness.

The results of comparative pharmacological tests made with the four products A. 1-p-chlorobenzhydryl-4-[Z-(Z-hydroxyethoiry)-ethyl] piperazine B. 2-phenyl-3- diethylaminomethyl-4 diethylamino butanol-l,

C. 2'-phenyl-3-(N-morpholino)-methyl 4 (N morpholino)-butanol-1 D. 3-phenyl-4-dimethylaminomethyl 5 dimethylamino pentanol-l are-reproduced in the table given below.

The figures given for the ataraxic activity er s represent the activity of the products, taking as a basis the figure of 100 for the product A. The figures given for the secondary eifects represent the percentage of cases in which drowsiness has been clinically observed. The toxicity per os L.D. 30 represents the number of milligrams per kilogram of animal which kill 30% of the animals subjected to the tests.

Products A B O D Ataraxic activity per os 100 100 100 167 Secondary efiects clinically observed (drowsiness), percent :25 ml ml ml Toxicity per os L.D. 30 800 750 4, 000 2, 000

The products of the invention are prepared by reducing the ethyl esters of the corresponding monocarboxylic acids in accordance with the reaction R-0.H.-oH-(0Hi)..-1-Co0c,H R-cH4-cH-(cm)..0H

The reduction of the ethyl esters is carried out by'dne ates atent 2.934.534 Pa tented Apr. 26, 1960 by means of sodium amide in accordance with the-reaction The nitriles are obtained by reacting ethylene oxide with the appropriate nitrilein accordance with the reac- The ethyl esters used in the preparation of the products of the invention are obtained by hydrolysis of the corresponding nitriles, followed by esterification of the acids formed. Thus, the esters used for preparing products of the Formula I, in which n=l, are obtained in accordance with the following reactions citrus x The esters used for the preparation of products of the Formula I in which n=3 are obtained in accordance with the following synthesis CHx-N X The nitriles used for synthesizing the esters employed as starting products for the preparation of the products .of the invention, are obtained by the methods usually followed for the preparation of nitriles. Thus, for example, an R-phenylacetonitrile is treated with 1 molecule of a derivative CHz-N X Hal-CH in accordance with the reaction Example 1 .--2-phenyl-3-diethylaminomethyl-4- diethylamino-butanol-I I In a nitrogen atmosphere, an ethereal solution of 0.15 mole of ethyl 2-phenyl-3-diethylaminomethyl-4-diethylamino-butyrate is added dropwise with agitation to a suspension of 0.2 mole of lithium-aluminum hydride in 500 cc. of anhydrous ether. The mixture is heated under reflux for 2 hours.

The reaction mixture is cooled and the complex formed is hydrolyzed by addition of an aqueous sodium-potassium tartrate solution. The ethereal solution is decanted, dried over sodium sulphate and the solvent is evaporated off. -The residue is distilled under a high vacuum. 2- phenyl-3-diethylamin0methyl-4-diethylamino butanol 1 having a boiling point of 135 C./0.05 mm. Hg is obtained in the yield of 95%.

Example 2.2-phenyl-3- (N-morpholin'o) methyl] 4- (N -mrph0lino) butanol-I .mm- CH-CHQQH GH-CHaN To a suspension of 14 g. of finely divided sodium in 50 cc. of toluene, maintained at about 60 C. is rapidly added a solution of 0.1 mole of ethyl. 2-phenyl-3-[(-N- Example 3.--2-phenyl-3-dimethylamin0methyl 4 dimethylamino-butanol-l CQHA CHCHQOH 0.5 mole of ethyl 2-phenyl-3-dimethylaminomethyl-4- dimethylamino-butyrate in 100 cc. of ethanol containing 10 g. of copper chromite is heated with agitation in an morpholino)methyl]-4-(N-morpholino)-butyrate in 130 autoclave at 200 C. for 3 hours under a hydrogen pressure of 200 atmospheres.

The catalyst is separated ofi in known manner and the solution is fractionated by a distillation in vacuo. 2- phenyl-3-dimethylaminomethyl 4 dimethylamino-butanol-l having a boiling point of 130-132 C./0.l mm. Hg is obtained in a yield of Example 4.-3-phenyl 4 l(N-m0rpholin0)methyl]-5- (N-morpholino) -pentanol-1 CsH5-CHCH:-OH2OH To a suspension of 0.2 mole of sodium amide in cc; of toluene is added a toluenic solution of 0.2 mole of 2-phenyl-3-[ (N-morpholino )methyl] -4-(N-morpho1ino)-butyronitrile, and the mixture is heated under reflux for 1 hour.

The solution is allowed to cool to about 80 C. and 0.2 mole of gaseous ethylene oxide is added in the space of 90 minutes.

The toluenic solution is washed with water and fractionated by distillation. The 3-phenyl-3-cyano-4-[(N- morpholino)-methyll-5-(N-morpholino) pentanol l is obtained in a yield of 40% (B.P. 234 C./ 0.02 mm. Hg).

This nitrile is decyanided in xylenic solution by heating for 12 hours with a large excess of sodium amide. After :washing with water, the product is distilled and 3-phenyl-4-E(N-morpholino)rnethyl] 5 (N-morpholino)-pentanol-l having a boiling-point of 197 C./0.01 mm. Hg is obtained in a yield of 65 Similarly, from 3-phenyl-3-cyano 4 dimethylaminomethyl-S-dimethylarnino-pentanol-1 (B.P. 180-185 C./ 0.05 mm. Hg), there is prepared 3-phenyl-4-dirnethylam-intzunethyl-S-di-methylamino-pentanolv having the following formula 1 Example 5 I The following products were obtained by reduction of the corresponding esters by one of the methods of Examples 1 to 3.

2-pheny1 3 dibutylarninomethyl 4 dibutylamino-butanol-l c upon-onion H-oHiNwmm CH2N(C4 '9)a B.P. 163 C./0.01 mm.'Hg.

2-phenyl-3-[(N-piperidino)-methyl] 4 (N-piperidino)- {IE-CH2 CHzN B.P. 176 C./0.4 mm. Hg.

2-o-tolyl-3-[(N-morpholino)methy1] 4 (N-morpholino) butanol-l OH-CHzOH HZN 0 B.P. 210-215 C./0.005 mm. Hg.

4-pheny1-5-[(N-morpholino)methyl] 6 (N-morpholino) hexanol-l CaH5-CH-CHzCHzCHzOH B.P. 187 C./0.0l mm. Hg.

For preparing these products, one of the following new substances may be employed:

Ethyl 2-o-tolyl-3-[(N-morpholino)methyl] 4 (N-morpholino)-butyrate CH-C O O CaHs (LE-CHrN E) For obtaining this ester, a nitrile is first prepared by reacting 1:3-di(N-morpholino)-2-chloropropane with the monosodium derivative of o-tolylacetonitrile. This nitrile is thereafter hydrolyzed and the acid obtained is esterified by ethanol.

B.P. of the nitrile: 205-210 C./0.0l mm. Hg.

B.P. of the ester: 192-194 C./0.05 mm. Hg.

Ethyl 4-phenyl-5-l (N-morpholino)-methyl] 6 (N-morpholino)hexanoate C H5CHCH OHiC o o 0 H;

(LE-C HEN o CHEN 0 is then cooled and taken up in benzene and washed with water, and the solvent is evaporated off. By rectification of the residue in vacuo, 4-phenyl-4-cyano-5-[(N-morpholino)methyl]6-(N-morpholino)-heXanenitrile is obtained in a yield of 82% (B.P. 237 C./0.03 mm. Hg).

This nitrile is decyanided and hydrolyzed by prolonged heating with a 70% sulphuric acid. The mono-acid formed is esterified with ethanol in the presence of sulphuric acid. Ethyl 4-phenyl-5-[ (N-morpholino)methyl]- 6-(N-morpholino)hexanoate is obtained in a yield of 30% (B.P. 189 C./0.03 mm. Hg).

I claim:

1. New diamino derivatives of phenylalkanols selected from the group consisting of compounds having the general formula wherein R is a member selected from the group consisting of a hydrogen atom and a methyl radical, n is an integer from 1 to 3 and N X is an amine residue selected from the group consisting of dialkylamines with lower alkyl radicals, piperidine and morpholine.

2. As new compound 2-phenyl-3dirnethylaminomethyl-4-dirnethylamino-butanol-1 3. As new compound 2-phenyl-3diethylaminomethyl- 4-diethylarnino-butanol-l.

4. As new compound 2-phenyl-3dibutylaminomethyl- 4-dibutyl amino-butanol-l.

5. As new compound 2-phenyl-3-[(N-piperidino)- methyl] 4- (N-piperidino butanol-l.

6. As new compound 2-phenyl-3-l(N-rnorpholino)- methyl] 4- (N-morpholino) butanol- 1 7. As new compound 3-phenyl-4-[(N-rnorpholino)- methyl] 5- N-morpholino p entanol- 1 8. As new compound 4-phenyl5-[(N-morpholino)- methyl] 6- (N-morpholino hexanol-l.

9. A process for preparing new diamino derivatives of phenylalkanols selected from the group consisting of compounds having the general formula H-CHr-N X wherein R is selected from the group consisting of a hydrogen atom and a methyl radical, n is an integer from 1 to 3 and N X is an amine residue selected from the group consisting of dialkylamines with lower alkyl radicals, piperidine and morpholine, which comprises reducing into the corresponding alcohols ethyl esters of the general formula 10. A process according to claim 9 wherein the reduction is carried out by means of sodium in alcoholic medium.

11. A process according to claim 9 wherein the reduction is carried out by means of lithium-aluminum hydride.

12. A process according to claim 9 wherein the reduction is carried out by means of molecular hydrogen in the presence of copper chromite.

References Cited in the file of this patent FOREIGN PATENTS 649,981 Great Britain Feb. 7, 1951 

1. NEW DIAMINO DERIVATIVES OF PHENYLALKANOLS SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULA 